Our poor understanding of the molecular mechanisms that underlie the cognitive and behavioral impairments that characterize Alzheimer?s disease stands as a critical barrier to identifying effective preventative measures and treatments for Alzheimer?s disease. This project seeks to address this gap in our understanding by examining the ability of enzymes that control the methylation of the serine/threonine protein phosphatase, PP2A, to control the pathological actions of tau ? a central component in the molecular etiology of the disease. PP2A is a heterotrimeric enzyme that exists in multiple isoforms with different expression patterns and substrate specificities, and the activity and composition of these isoforms is regulated by multiple mechanisms including protein methylation. PP2A methylation is controlled by an evolutionarily conserved mechanism involving the competing actions of a dedicated methylesterase and a dedicated methyltransferase ? PME-1 and LCMT-1 in mice respectively. In preliminary studies, we found that transgenic over expression of LCMT-1 protected mice from cognitive impairments caused by acute exposure to soluble tau aggregates, while PME-1 over expression increased sensitivity to these impairments. In this proposal, we will build on these observations by pursuing the following specific aims: 1) Determine which aspects of tau pathology are affected by increased PME and LCMT expression levels. 2) Test the hypothesis that inhibiting PME-1 protects against tau related impairments. 3) Test the hypothesis that PME and LCMT expression levels affect sensitivity to tau by altering the proportion of Ppp2r2a-containing PP2A enzymes. These aims will be addressed through a combination of behavioral, electrophysiological, and biochemical techniques in genetically modified mice. The data obtained from these experiments will identify the mechanisms whereby methylation of the catalytic subunit of PP2A controls the development of tau-related impairments in Alzheimer?s disease, and test the possibility that interventions that target this pathway could constitute an effective therapeutic approach for their prevention or treatment.